The goal of engrafting human cells into other species has been pursued for six decades. This goal remains and there are multiple labs across the world that are using, and improving humanized mice to address a range of high impact biomedical questions. However there is a need for developing systems in species that more closely resemble humans in size, physiology and longevity. The pig offers an exceptional and perhaps the best system for this purpose. Pigs are widely available and the life span, and cell and organ physiology more closely approximates those of human. Pigs are readily bred, born in litters and amenable to genetic engineering. Additionally, recent advances in gene editing have allowed the development of complex multi- transgenic pigs at very high efficiencies. We propose to introduce changes into the genome of pigs so as to enhance their ability to host human cells without rejection. We will focus on reducing phagocytosis of human cells by pig macrophages, enhancing the bone marrow stem cell niche so human cells can engraft at higher efficiencies, and providing a cytokine environment that favors human versus pig cells. Completion of these aims will result in the development of a new large animal model capable of robust and functional engraftment with human stem cells.